Note: Descriptions are shown in the official language in which they were submitted.
Field of th~ Invention
~ he pre~e~t i~e~tio~ relates to medicine and, more
particularly~ to a novel pharmaceutical compositio~ for
the treatme~t of c~rdio-vascular ~ sease ~uch a~ c~rdiac
in~ufficiency at valvular ~e~ects~ m~ocarditises, cardio
sclero~is, i~chemic heart disea~e, rhythm di~orders
(arrh~thmia) of diff~rent genesis.
Background of the Invention
At pre~ent the principal selec~i~e cardiotonic pha~a-
ceutical preparations are cardiac ~l~co~ides~ ~he~ cover
preparation~ of digitalis, as well ~ chni8, ~tropha~thus
~nd may lily (cf. M~Yu~Mashkov~ky~ Ph~rmaceutical Pr~p~rs~
tion~, M., Meditsina Phblishing ~ous~ 1977)o
~ a~ic disadvantage of gl~coside~ i~ their low therapeu
tical indcx. Overdosage o~ the pr~paratio~s c~u~a~ seriou~
complic~ion~: acute brad~cardia~ pol~to~e extra~y~tole~
bigemi~y~ trigsmin~ deceleration of atriova~tricular
condition 9 ~tricul~r ~lutter ~nd dia~kolic c~rdiac
arrestO
A~ e~se~tial di~ad~tage r~ide~ o in the ab~ence
of a di~ti~ct correlation bet~en the pr~paratio~ concen-
tr~tio~ i~ blood and the e~fect obtainedO ~uxthermore~ gl~
cosides frequentl~ caus~ irritatio~ of mucous ~embrane of
; the ~tomach a~fect vomiting center re~ulting i~ dy~peptic
di~turb~ce~
~ ler~e group of preparatio~ for the treat~e~t o~
.:
s~
cardio~va~cular di~eal3es is constitu~ed b~sr anti~rrhythmic
prep~rations~ Orle of the mo8t widel;sr emplo~ed among them
i8 novocainamide which is ~;ucce~3sfully Rdmini~tered at
~ariou~ kinds oî rh;stthm di~;turbances i~cludi~g e~ tra~ystole.
~Iowe~er, ~ven thi~ pre ?aration can cause ~ide effects ; ge
~eral w~akne~s; headache, nau~ea, vomiti~g, iD.somnia, dys-
peptic phenome~ d, at the i~travenou~ mod~ GI adminis-
tr~tio~,, possibt e dovelopment of ~ c~rdiogenic ~hock.,
Eurthermor~ ~ due to possible inhibitio~ of m~oc~rdial con-
tr~ctibilit~r and reduction of arterial pre~s~re in the
c~se of m~ocardial i~fsrction the preparation ~houl~ be
admini~tered with ~reat cautionO
A ~imilar di~ad~a~ e is ixlher~nt in hig~ly e;~fi-
cie~t preparation3 Aimalin a~d Et~moæin ~eth~l ester of
2-carbamic acid 10-(3-mor~hol;srlpropiongl)phenothiazino
~;ydrochlorid~) which al~o lower contr~ctile properties of
m,yoc~rdium ~hus cau~i~g reductio~ of arteri~l pre~aure
snd complicati~g their admi~istratio~ ak c~rdiog~nic ~hoc~
~nd h~rpote~ion~
,~-Adre~oblocker~ (Ideral, Benzodixin9 O~renolol)
al~o h~ve ~ ~umber of negati~e ~ide effect~O ~hese compo-
u~d~ ~re highl~ toxic (LD50. ~ Inderal i~ 30~50 m~ g for
whit~ mice), provide a negative illotropic ~ffect; they
are contrsi~dicated at ~ome heart dish~e~ ~uch ~8 ~inus
br~d;yc~rdi~9 atrioventricul~x bloc~, cardiac insufficien-
cy, bron~hi~l a~t~:ma ~ diabete~ mellitu~ and the like,.
~ o cut ~hort attac~c~ of bre~st pang use i6 ~uccess
full;sr made of org~nic ~itrst~ amo~; which nitro~lycerin
- ; 3
, .
, .... . . . . .
~ 5~ ~
has en~oyed mogt e~tensi~e application. ~he latter prepar~-
tion i~proves to~us of coronar7 arterie~ ~nd ~djust~ re~is-
ta~ce of perlpheral ~e~sel~, thug facilitati~g the heart's
fu~ction of blood di~charge î~to aorta.
~ neg~tive propert~ of nitroglicerin is a short dura-
tio~ of its effect and abilit~ of cau~ing 8trong cephalal-
gia due to ch~nging tonu~ of skull ~eins~
Al~o known i8 a na~urally-occurring ~etabolite
~-but~robetain featuring ~ broad range of biolo~ical acti-
vity including the effect on cardio-~ascu?ar sy~tem (~ature,
18~,3~8, ~959). HoweYer, ~-but~robet~in is rapidl~ metabo-
li~ed in the orga~ism into carniti~e a~d, due to this ~act 9
i~ pos~e~se~ onl~ a short-time effect~
, . i
It is an ob~ct of the present inve~tion to provide a
novel pharmaceutical preparatio~ for the treatment o~ car~ I
dio~a~icular di~iea~e~i which would ~eature a low toxicity9
higher e~ficie~cy ~nd longer effect, and to eliminate ~ide
. phenomena characteristic Or kno~n prep~rati~s i~tended
~or the ~re~tment of cardio-vascular d~sea~es. .
D~tailed De~cription Or the Invention
., . ~
~ he pha~maceutical co~po~itio~ according to the preA
sent i~rention i~ no~el snd hitherto unk~ow~ in the art~
~ hi~ object is accomplished by tha~ ~he novel pharmar
ceutical composition for the treatment 9~ cardio ~a~cular
di~ea~es comprising an acti~e pri~cipl~ and a pharmaceu~i-
c~lly scceptabl0 dilue~t contain3 a6 ~he acti~e principl~,
~ 4 - :
1. :,....... .
. , :
. ~, ~, . . ........ .... . . .. .
accordi~g to the pre~3e~ inverLtion~ 3-(2~2~2~t~cimeth~1~;ydra-
zinium) propio~te of the following formula:
(c~3)33~ C~2Cl~G~ ) ~2r
In the ca~e of U8~ ; the m~dicated compound a~ injec-
I;ions it co~ta~s the active principle i:n an amou~:Lt of 5
to 40~ b;y w~ight and, as th~3 pbarmace~atic~ll;r ~cceptable
diluent ~ ~olYent di~tilled water ur ~ otonic solu~
ti~ O
Whell to be admini3tered a~ t~blets or capsule~, it
contEIins the ~ctive principle in ~n amount of 00~ o 0,. 5
g per tablet or c~p~ule~,
Special e~perime~tal studies have sho~ that the
afî ect o~ the prep~sr~tion is ba~ed on its abilit;5r of dila
tating coronar;sr ~rteries, thu3 accelerati:n~s a~imilation,
b;y myoc~rdium9 of ener~-supplyi~g cub;tance~ a~d providing
a pociti~ve e~fect on mitochondrial apparatu6 of m~oc~rdium
cell which eventu~lly contribute~ to ~ pronounced de~relop~
ment of a po3itive inotro~ic ~fect of the cardiac mu~cle~,
~ he ph~ac~utical prep~ra~ion accordin~ to the pre~
~nt ~ention caII be u~eîul in the trea-~ent of ~uch di ~-
~se~ a~ heart in~uf~icienc~r~ v~lcular de~ec t~ " m;yocarditi-
~e~ 9 card~o~cl~ro~i'8, i~chemic :heart di~e~a q rh;~thm di~
~urbance~ o~ differe~t y;ene~isO In the~e casa~ it~ efîect
i~ ~uperior to th~ therapeutic action of other pharmaceuti~
c~l preparation~ includin~;9 for exampl~, cardiac gl~co~de~,
J~blocker~, Carb~crome~eO Especially pronou~ccd therapeu-
tic xe~ult3 h~ve been ob~erved in ~e ca~e of chronical de-
compen~3atio;n at rheu~aa~ic val~rul r defects 7 acu-~e circul~-
,
~o:~y in~ufficiency at my~oc8rdi~1 in~arc-tio~O Also positi~re,
though les~ pro~Lounced7 effect is obser~ed upon ~mini~tra~
tion of khe pharmaeeutic~l prepar~tion according to the
preaent invention i~ ~hc case of paxo}c;y~mal tach~yoardia,
fibrillation, ~V block, parox~m~O The preparatio~ accor
din~ to the prese~t invention ha~; been tested in experiments
on ~nimal~ ~nd in clinic~ on pa~i0n~3 with v~xious kinds of
pathology~,
~ hus, the effect of the preparatio~ accordi~g to the
pre~ent invelltion hs~ bee~ ~tudied relatiYe to vari~tion of
~he arrhy~hmogenic and lethal doses oî calcium chlorids.
thç experi~e~t was carried out o~ white mice of both ~exes
w~ighing '19-~8 g which were narcotized by urethane a~d ECG w~
remetered in tran~thoracic lead. A ;~ ~olution of calcium
chloride WhB ~dministered to tha te~t ~nimals into the tail
~rei~ at a co~st0~t rate (0u1 ml for 15 seco~ds). q!he ~verage
do~e o~ c~lcium chloride cau~ing appearance of srrh~thmia
and he~rt ~rre~ wa~ determined~ In the te~t group~ the ~tu~
die~ compoulld~ were ~dmini~tered 45, 60, '120~ '180 and 240
minutes befor~: the be~ ing of admini23tration of cslcium
chlorid~ ~able 1 ) ~, It h~s been round t:h~t even ~ gle pre-
limin~ry ~dmini~r~tio~ of the preparation based on 3-(2,2,2
t;rimethylh;~ zinium~-propionate intraperitoneall~ i~cresses
ths arrh;~thmogenic and lethal dose~ of calcium chloride.
Though the prior art preparatiQ:~s :~o~oc~inamide and quini-
d:Lne in ~ppropriate dose~ c~uses ~ more pronounced inor~ase
oî the arrh;ythmogenic do~e oï calcium chloride, th~ preparfl-
tion according to thc pre~ent inve~tion resul ts i~ a longer
-- 6
, ~
s~
a~tiarxh;ythmic effect alt a ~ub~3t~ntially lower toxicitg
(Tsble 2).
~ he snti~rrh~thmic activity w~ ~ atudied in experi-
ments on whit~ ratfi of both ~;e~es with ~ ma~ of 190 to
2~0 g ~arcotized b;y ureth~ne; for the~e ani~als :E:CG wa~
r~corded. I~to th~ f emoral v~in OI the rat~ aconitine wa~
irltroduc~d ~t a con~tan~ rate a~d it~ arrh;ythmogenic and
lethal doses were determined 13lo~g with their variation
under the protective effect of t}le preparation ~ccording
to the present in~rentio~. It ha~ been rou~d that the pre-
p~ration ha~ ~ pronounced protective ePfect ~l~o at the
peror~l mode of ~dmini~tr~tion t~able ~0
~ hus~ proph~lactic peroxal ~dministration of the pre-
paration at the dail~ dose of 25 mg/kg during one wee~ ~ub-
~tantiall~ increa~e~ ~he arrhythmoKenic and leth~l dos~s Or
~conitlne (by ~8.7 and 27.6% re~pecti~el~ Jected 1~
hour~ ~fter the last ~dmini~tr~tion of the preparation of
the in~e~tionO At a moro la~ting admi~i~tr~tion protective
proper~ies of the prep~ratio~ ~re ~ronounced even more
clearly ~ble 3)~
~ he ef~ect of the prepar~t~on a¢co~ding to the pre-
~ent in~ention on the ~ri~tion o~ the arrh~thmogenic
do~e o~ Strophanthin G wa~ studie~ in experiments on rab-
bit~ of both se~e~ wi~h a maa3 of 0~3 to 0~6 kg admini~te-
red with Stro~ha~thin G i~ the do~e of 60 ~g~g into the
marginal ~uric~l~r ~in and, after e~er~ 5-10 minutes, at
do~e o~ 5~10 ~g~kg till the appearance of ~ ~table ~ent-
ricular extras~6toleO I~ the test ~roup~ 20-30 minute~ be-
, - 7 -
.. .. . . . . ... . . ... . .... . .
.
~ f~3
fore administration of the glycoside a solution of 3-(2,2,2-
trimethylhydrazinium) propionate was propholactically ad-
ministered intravenously, the ECG was recorded in II standard
lead.
It was found that in the dose of 10 mg/kg the pre-
paration increased the arrhythmogenic dose of Strophanthin
G from 67+9 to 90-15 ug/kg (Table 4). At a further in-
crease of the dose of the preparation to the present inven-
tion its protective effect was increased too.
Variation of arrthythmogenic and lethan doses of CaCl~with time after administration of the studied phar-
maceutical compositions in experiments on mice.
Table 1
N Pharmaceutical Preventive Ti~e, minu-tes _ _
os composition dose, mg/kg
intraperi- 45 60
toneal adminis- arrhy- arrhy-
tration thmo- lethal thmo- let-
genic gonic hal
Doses of CaCl
~ 2~
1 2 3 4 5 6 7
~- __ _
In~ection form of 1091.5 101.7 103.4 122.2
the preparation o~
~he invention, 40~
solution of 3-(2,2,
2 2-trimethylhydrazi-
nium)propionate in 30 106.7 122.8
0.3% solution of
NaCl
3 Novocainamide 10 114.16 120.8
125.16 143
.. . .. .. . ..... . . . ~ . ....... . .
4 Quinidine 3 128.9 147.7 104.5 117.8
120.84 138.54 119.~8 12~.2
, _ , ., . .. . . .. .
~;
Table 1
(contd.)
Control - 85 100.9
Nos. Time, minutes
S
120 180 240
arrhyth- lethal arrhyth- lethal arrhyth- lethal
mogenic mogenic mogenic
__
Doses of CaC12 mg/kg
1 8 9 10 11 12 13
_
2 111.9 130 110.1 116
117.5 130.2 121.9 128
.
86.85 104.5
3 93.16 114.9
. _
87.47 103.65
~ 94.5 117.6 88.7 115.8
.
Table 2
Acute toxicity of pharmaceutical compositions in
experiments on white mice at intravenous administration.
Pharmaceutical compo~ition LD50, mg/kg
Injection orm of the preparation
of this invention, 40~ solution
of 3-(2,2,2-trimethylhydrazinium)
propionate in distilled water 4,430(3,164.3-6.202)
-
.~,~.
Table 2
(contd.)
Novocainamide 112 (97.39-128.8)
Quinidine 58 (58.6-78.88)
- 9a -
,
~able 3
~tisrrhythmogenic ~ckivit~ of the preparation
according to the pre~ent in~en~ion ~t it~ repeated
admini~tration in experime~t~ on rat~0
Do~e of the harmaceutical Aconitine dose ~ariation,
compo~ition ~mg/kg) admi
ni~t~red perorally and Administr~tion for
contsining~ g:
1 wee~ 2 week~
3~(2,2 2-trlmethylhydr~ rh~t~ Lethal mogeYi~ hal
zinium~propion~te 0.400û
Silica with pux~ty grade
of 99u~ ~nd particle
~ize of 5-20 ~m 0.0340
potato ~t~rch 0.05B6
Meth~lcellulose 000024
M~gne~ium ~tearate 0.0050
~8~7 i 270~ ~2.,26 2~.7
100 , 5506 16.2 3406 9.7
.,
,
,
~ 10 -
.
`:~ . .,
~ble 4
Vari~tion of the arrhythmogenic dose of
~troph~nthin G under the action of the
pharmac~utica1 prepar~tion of the pre~0nt
in~ention
Prepara Arrh~thmo Duratio~
Ph~rmaceutic~l tion do~e~ genic dose of arrhy-
compo~ition mg/~g in- of Strop- thmi~,
travenou~- hanthing mi~utas
olution of the 10 90~15 '12~6
prep~ratioll ~coording ~ 25 ~lOG~'10 8~5
to the pre~e~t inven- 50 ~106~12 15
tion containing
3-~ ~, 2, 2-trimethylhydra-
zin:L~m)propion~te
~he sctive principle
- - 67~9 20+10
q~o i~veutigate the thex~peutic aff ect o~ the prepara~
tion ~ccording to the pre~ent i~ventiorl relatlve to th~
Stroph~nthin arrh;~hmia 9 another serie of expeximents
W~18 c~rried outO Stroph~nth~ was intr~e~ou~ dmini~
re~ to rabbits o~ both ~e~e~ with a ma~ o~ 3~0 to 3.8 kg
i~ the ~sener~l do~e o~ 80~ug/k~ wbich cauaed arrh;ythmia
within 40-60 mi~utes~ ~he te~t preparation was i~atravenou~
tered at the ~c~ground of ~rrh~rthmi~ i~ th~ teat
g~o~p O
It w~ found that ~he prep~ratio~ b~ed o~ 3-(2,2,2-
trimethylhydr~zinium)propion~te in a ~o~e of 1 ~o 3 ~ ~g
_, 11 -- '
~' ' .
~ 5~in the mfl~orit~ o te~ts ~lread~ within 1-2 minute~ ~fter
the intravenous admini~tr~tion ~emporaril~ arre~ted ventri-
cul~r tachy~rrhythmia cau6ed by Stropha~thin G in r~bbit~O
Chsnges in the comp~ex QGS~ were also reduced; after the
~dmini~tr~tio~ of th~ prep~ration in the dose of 5 mg/kg
the regular SynUS8l rh~thm w~s ret~ined ~or 12~5 minu~e~
o~ the average, whereafter arrhythmia wa~ gradually renewed,
but it could be again elimin~ted b~ a repeat~d administra-
tion o~ the prep~ration in a dose of 2-5 mg/kgO In such
case~ the ~inusal rhythm was retained for 15 to 30 minute~
and in the ma~ority of tests srrhythmia wa~ ~ever renewed.
Furthermor~, a~ ~periment wa~ carried out o~ narcotized
guinea pigs with a ma~ of 600-7~0 g to which Stroph~nthin
-~ w~s admi~istered into ~he f~moral vein in the total do~e
o~f 500 ug~kg.
~ he prep~ratio~ based o~ 3-~2,2,2-trimethylhy~xa~onium)-
propion~te was intr~enousl~ ~dministered against the back-
ground o~ arrhythmia in the te~t group. It was ~ound that ~
alread~ wi~hi~ 2-3 minutes a~ter the intr~venou9 adminiBtr~- i
tion the teBt prepara~ion temporarily ~rr~ted the ventri-
cular ~rrh~thmia caused b~ Stroph~nthin ~ e the gr~ph~.
~he ch~nges in the co~plex QRST were reduced ~nd the atxial
fibrillation di~appesred which wes demo~tr~ted b~ the appe-
~r~nce of the ~pt. ripple. I~ ~ome ca~e~ at a timel~ ~dmini-
~tration of t~e prep~r~tion in a dose of 2-~ ~g~kg it wa~
po~sible to al~o eliminate the atrio-ven~ricul~r bloc~
c~u~ed b~ Strophanthin Kv
~he graph illustrate~ the recordi~g o~ ECG of a guinea
p~,g,
- 12 -
~he ~fect of compound I on Stroph~nthi~ arrhynthmia
i~ ~;uinea pig~.
A ~ ECG of a gUi3D ea pig in IX standard lesd and time
mark of 1 8eCOnl~lo
:B - r~cording cont:inued.
1 ~ ~t~rting ~:CG
2 ~ ECG 3 minut~s a~ter administr~tion of S1;rophan~hiIl X
in the do~;e of 0. 5 m~ g
3 - ECG ~ minute~3 after admini~tratio~ o~ the preparat;ion
in the do~e oï 2 " 0 mg/kg
4 - recording of :3CG b;~r 8 minutea ls~t~r
5 -ECG 3 minutes after a~ tr~tion of the prepa~ation i~
the do~e of 5 mg/kg (18 minute~ af ter the begin~ing of
t~e experimeilt )
6 :E:CG p~tter:~ 15 mi~ute~ af~er admini~tratio~ o~ the
preparation in the do~e of 5 mg/k~
7 ~ ECG p~ttern 5 minutes after ~ repeated ~dminis~ration
of t~c preparation in t~e dose of ~ mg/kg
8 - :ECG patter~ 5 minutes ~ter the repe~ted a~mini~tra
tio~ of the p~ep~rat~on in th~ do~e of 5 mg~kg.
~urthermor~ 9 th~ prep~r~tion accordin~; to ~he present
invention wa~ t~ted Ior a ~peci~ic anti~rr~thmic &nd anti-
~ngi~l erfe~t~. ~or t~e purpo~e o~ compari~on also 1;ested
were prior ~rt ~ntiarrhythmic prepar~tio~s ~ guinidine,
novocain~mide 7 lidocain a~d a know~ antianginal agent -
c~rbo.cromene~ ~he ef~ect of the no~rel ph~r~aceutical com-
position ~ccording to the presen~ i~vention was studied
ol~ c~r~ w~i~shing 20973~.6 kg; the pr~p~ration wa~ u6ed as
- 13 -
::.
~t . ,. :, ~ . ,i `
~ ~5~
a ~ agueous ~ol~tion corlt~ini~g 3-(2, 2, 2-tri~ethylh;ydra-
zinium)propionate for th~ de~ermirla~ion of the thre~hold
value of electric ~ibrilla tion of au:ricle ~nd ventricle~.
At arti~icial resp ~atio~ a.~ter openin~; of thor~x ~d
perie~rdium needle-like eleotrode~ were applied to the
right auricula and ~pex of the left ~entricle. The irritation
w~ effected b~ ~iquaxe pul~es of 1 m. sO, 15 st/so ~he cur-
rent pa~sing through the he~rt w~8 graduall~ increased till
fibrillation~ ~ppe~red which were ev~luated b~ ECG and arterial
preesure on a ph;srsiograph s~r~ilable from ~arco Bio S;yskems Co.,
The studied compo~md~ wer~ adminiætered intravenouslyO ~he
results thus obtained are 8~10W~1 in ~ble 5 hereinbelow. It
was found th~t the ph~rmaceutical composition sccording to the
preserlt i~ventioll in a do~e of from 6 to 15 mg/kg upon intra
venous admini~tr~tion incre~ed by 40~55% the threshold of
alcctricaî ~ibrillation o~ suricle and ventricle~3 novoca-
inamid~ provided the ~EIme ~ffect in ~ dose of 40-55 m~/~cg.
Quinidine ~nd lidocain, though exerting their effect at
lower do~e~, had ~ ~ubst~ti~ r highsr toxicity.
For the compari~on of prep~r~tion~ 7 a~ the criterion
o~ the r~n~e o~ t~erapeutic eff ect, there w~e used the ratio
o~ the h~lf-leth~l do~e to the half effective dose ~D5of
;E:D5~) which was r~ferred to a~ the ~nti~rrh;ythmic ind~x~.
Th¢ ~llti33~;~thmic index of the pharmaceutical compo~ition
~ccord~ng t~ the preeent inven~ion in the Iorm o~ ~ '10% 60-
lution containin~;, as the a~-ti~e p~inoiple~ 3 ~2~2~2~tri-
meth~lhydr~inium~propionste ~443) for this paxticular t~pe
of ~rrh~thmia w~ subsk~nti~lly higher than the ~ntiarrhyth-
- 14 ~
.
5~
mic index of quinidine (26)~ lidoc~in (1~) and novoc~insmi-
de (2.3)~ Th~ comparative study o~ th~ antiarrh~thmic aciti
vit~ of ph~rmaceutical prep~ration8 using acotine model of
arrh~thmia w~ effected in experiment~ on white r~ts weigh-
.ing 190-240 g. The test prepsrations wer~ ad~inistered in
traperito~eally ~0-40 minute~ before ~dministration of aco-
nit.ineO ~he results are shown in ~able 5 hereinbelow.
For this ~odel o~ ~rrhythmia the ph~rmaceutical prepa-
ration according to the pre6ent inventio~ show~ a sub~tan-
ti~lly higher activity as compared to ~he known ~ntiarrhythmic
prepMration~O ~hus; the anti~rrhythmic index for the pharma-
ceutical preparation according to the pre~ent invention was
3~, whil~ for gui~idi~e and.novocai~amide ~hese ~alues were
16 ~nd 2.5 respectivel~J A~ the third model of arrh~thmia the~
re was u~ed ~trophanthin arrh~thmia in guinea pigs. ~o guine~
pig~ with a ma~ of 420 to 7~0 g Strophanthin-K wa9 admini~
~exed in the do~e of 450 ~/kg. In the oontrol ~roup this
dose o~ Strophanthin caused ~ppe~r~nce of arrhythmia a~ i
de~th o~ th~ anim~].s wit~i~ 1Z~20 minutes~ ~g~in~t the
background of arr~ythmia the test prepsrations were adminis~
t~red intr~ve~ousl~ ~h~ result~ thus obt~in~d are sho~n in
~ble 5 hereinb~low. ~he test~ h~ve ~hown ~hst the intra~e~ou~ 1.
~dministr~tion of the pharm~ceuticsl Gomposition ~ccording '.
to the pre~ent inventio~ and novoc~n~mide cut~ ~hort the .:
Strophanthin-induced arrhythmia in guine~ plg5 for 5-20 minu
te~ in 6 experime~ts out o~ 8, wherea~ the administratio~
o~ lidoc~n ~nd qu nidi~e cause~ improvement, accordlng to
ECG data, rOr only 0.5-3 mi~ute~ in 4 out of 7 and in 4 out
o~ 8 ~im~l~ re~ecti~el~. ~5
.
~ ha stud~ of the preparation according to the pre~ent
invention for arterial pre~sure.g breathing and hemody~amic
effects of ~orepinephrine~ neoepinephrine, no~oepinephrine 9
~cet~lchcline and histamine wa~ carried out i~ e~periments
on cats with a mass of 2~8 to 4.0 kg n~rcotized by chlor~se.
~here were then recorded the ~nimalsl arteri~l pressure~ res
piration ~nd ~CG on a phy~iograph pro~uGed ~ rco Bio-Sy~-
tem~ Co.
~nti~rrh~thmic ~cti~ity and aeute toxicity of the
te~t ph~rmac0utic~l compo~ition~
~able 5
~D 0 mg/kg ~ ~D5J~D50/
~0~ Ph~rmaceutical
compo~ition Electric irri- Aconitine ar- i~
t~tion of cat 1 8 ~hgthmia in
he~rt r~t~ '
.__________ ~_____~__~___ _ 4
10% ~queous solution of
the ph~rm~ceutical pre~ 5
2 p~r8tion of this i~ven
tion for i~jections
containin~ 3-~2,2 2-tri
meth~lhydr6~inium~pro-
pion~te as the active
principle 10~3.5 ~433J ~205~2.5/354
3 Quinidine 2~6tO.5 ~26~4.3~006 ~16J
4 Novocai~mide 46.0~60~ J2/ 45.0~5.0~2~5J
5 L1docai~ 3.o 0~3 J~3~
.
- 16 -
'
~abl e 5
~contO)
}:Dso mg~k~ D50/~D5o~ Acute to~i-
~o~ ci~
Strophanthin ~rrh~th~ white mice
mi~ in guinea pigsnous admi-
nistration,
I,D50 m~/k~
2 7.8~2~3 /568/ ~943
(3,164~3~69202)
3 2 0 3~0 ~ 4 ,~30~ 68
(5~"6-7~.88)
., i.
11~
7 ~ 2/ ( 97 ~ 9~128 . 8 )
;
f
3 . 8~0 . 5 /11/ 40
~3~.3;4~)
' ~
~t was fou~d that in doses of,0.5 to 2.0 m~3/kg the f~
prep~r~tion ~dministered intrave~ousl~ did ~ot re~ult i~
~ny essential ch~nge of arterial pre~sure, pul~e ~reguency
and respir~tion. ~hs above-~peci~ied do~e~ of the prepera
tlo~ neither chsnged the leYel of~ respon~es to biogenio ami~
nes. At higher dose~ of the preparation (15-25 mg/kg~ there
w~ observed ~ ~hort-time reduction of arteri~l pres~ure
by 5-20 mm ~g which in some c~;es wa~ changed to a more
l~tinK (5-12 minutes) i:~crease of ~rterial pressure by
5-10 mm Hg as compared tv the initial valueu ~t the same
t~me ther2 wa6 ob~erved a short time increase of the res- ;
~ 5~
ponse to hist~mi~e (by 5-10~) and ch~nge in response to
~he ~dmini~tration of neoepinephxine (by 5-1~%) and ~ce~yl
choline ~by 10-15%)q A ~ur~her i~cre~se Or the prep~r~tion
dose did not c~use changes of blood pres~ure or respon6e
to the admini~tration of biogenic amines.
~ here were also carried out comp~rative ~tudies of the
~ffect on coron~ry circulation exerted by the pharmaceuti-
cal compo~ition according to the present invention and car-
bocrD~ene~ ~he pharmaceutical compo6îtio~ according to the
inventio~ i~ used in the form of a 20% in~ection solution
contsini~g 3-~(2,2,2~trimeth;~1h~dr~zinium)propion~te a~ the ac-
ti~e princip~e in a 0O~% ~olution of sodium chloride.
I~ ~cute experiment~ o~ narcotized ~ats with a mass of
from 2.9 to 4.1 kg under the conditions of ~rtificial re~pi-
r~tion ~rteri~l pressure w~ recorded in common carotide ,
arter7, centr~l venou~ pre~sure - in right ~uricle, volu~e
rate o~ blood ~low in the ~scending aortic arch and volume
rate of t~e coronar7 blood flow~ At the sa~e time there was
recorded the content of oxyhemoglobin in venou~ coronar~
blood~ ~he compar~tive dat~ on the efficienc~ of the pharma-
ceu~ie~l compo~ition according to the present invention ~nd
that of carbocro~bne are ~own in ~a~le 6 hereinbelowu
it i~ 8e~n from the ~ble, the ph~rmsceutical compo-
8ition ~ccording to the presenk invention ~nd c~rbocromene
i~ e~ui~alent dose3 i~crease9 over a long timel th~ volu~e
rate of coronary blood flow at a low effect exerted on the
~rterial pre~sureO oth preparation~ do not change'or o~l~ :
~lightl~ rea~0 the c~rdi~c output. ~urthermore, ~he pre-
'I ~
,
',`' , .' . '
par~tion acç~rding to the present in~ention, likewi~e c~rbocro-
mene, lastingl~ increase ~aturation of venous blood of corona-
r~ sinu~ with oxygen, w~ereag toxici~ of the preparation of
thi~ invention'i~ b~ 12 ~ime~ le3~er th~n th~t of carbocrome
ne. ~or thi~ rea~on, the therapeutical index of the novel
pharm~ceutical compo~itio~ i8 by approximately 3 time~ hi~her
(314 v~. 130)o
~ here were ~l~o carrie~ out the tests of ~llerge~ic ca
p~city of the prep~ration accordin~ to the invention; the
test results have ~ho~n that the prepar~tion does not cau~e
irritation of ve~sel walls when aclministered intravenously;
neithex it cause~ aller~ic re~ponses both at i~travenou~ and
pero~al modes of ~dministration e~ther upon ~ si~le or long-
time (up to ~0 da~) admini~tra~io~ thereof~
~ e prepar~tion doses of up to 10,000 mg/kg in e~peri-
ments on white rats administered perorall~ on ~n~ day of
pregna~cy cau~ed no embr~otoxic or teratogenic effect6,
~he stud~ of the mut~genous ~ctivit~ of the preparatîon
based o~ 3-(2,2,2~trimeth~lhydrazinium)propionata dih~dr~te
on ~ruit flies and ~almonellae h~s ~hown that the preparation
of the pre~ent invention doe~ not h~ve mutagenous acti~it~J
Pharmaceutic~l preparatio~ based on 3-(2~2~2~rimeth~l-
h~r~zinium)propionate dih~dr~te are stable in ~tor~ge at
ths tempex~ture o~ ~5C for flt le~8t two yearsO
~ he prepsration h~ been ~tudied o~ more than 65 pati-
ents suffering from YariOUs patholoEy of the cardio-vascular
sy~tems such a8 heart rbythm disturb~nce~ ~arrhythmia) of
different etiology, i~chemic hesrt disea~e, ~tenocardia,
athero~clerosi~0
: _ ~9 _
,
qhough the indication~ for admini~tration of the
prepax~tion were con~iderabi~ low, during clinical tests
it wa~ ~dministexed ~ainly to patients with ischemic
he~rt dise~se (IHD)o Given hereinafter are the results of
~n~lysis of the preparation a~icie~cy in 20 men and women
ag0d from 25 to 50 ~ear~.
All the patients h~d typical s~enocardia (angin~ pec-
toris) ~ttacks, two patients h~d pronounced p~tholog~ of
coronary ~rt~ries revealed by coronarograph~ and in 5 pati~
ents - a l~rge-focu~ myocardi~l infarction in ~n~mnesis with
p~thological 0 in ECG~ ~11 patient~ were peror~lly ~dminis~
tered with the prepax~tion i~ ~ dose of 20 to 40 mg of the :~
~ctive principla per k~ of the bodyweight which each pati-
e~t was given during the dayti~e with meals for 4 wee~s
altogether which was 4~-96 g on the a~er~ge per the treat-
ment cour~e.
~ he fo~lowing hemodgnamic~ parameters were studied.
r~te of the heart's ~aat (R~B), electroc~rdiogram (~CG)~
~11 kinds of ~rterial pr~ssure with the curve recording on
~ Mechanocardiograph 063 ~Savitsky' 8 model), beat ejectio~
accordi~g to the Wrem~er-Ranke metho~t ~peed o~ pulse w~e
prop~ation, ph~e an~lysis of the left ventricle sy~tole
o~ ~n in~trument Mingogrsph M 341 a~ well ~ amplitude
time parameter~ (volume rate of e~ection VRE, speed of
pr~ure ~row~h (SPG)~ rste of heart rela~ion (R~R~).
Duri~g the investi~ation the patients suffering from
I~D continued their acti~e way of life, all other medicated
compounds were calcelled, except for ~itroglycerin tabl~t~
when required~
20 -
~able 6
~emodynamic characteristic~ and acut~ toxicit~
of the p~armaceutical preparatio~ containing
3 (2,2,2-trimethylh~drazinium)propionate a~
the active principle and the preparation
C~rbocromene~
Pharm~ceutical Dose~ Volume rate of
arterial pre~sure, %
No~ preparat1on mg/kg
Perce~t Increase
. of incre~- duration~
. se - mi~utes
1 ___________ ~Z________ ~ 4
20% in~ection solu- 2 15 20
tion contai~ing
2 3-(2,2,2-trimethyl- 10 40 45
hydrazinium~propio-
nate as the active25 55 7
principle in 0.9
fiolution of NaCl
3 C~rbocromene 0O5 30 35
2 45 5
- 21 ~
Tabl a 6
(cont. )
Change of Change of Change of Ac~te toxicit;sr
~: arterial heart out- central for white mice
os pressure, putg ~6 venou~ at intraperito-
96 pres~ure 5 neal administ
% . ratio~, ID
mg/~g
6 ~Z 8
~ -5 ~~ +5 0 7 9 ~50
2 (~ '1.6+9,4~0)
~5 '10 -5
-8 - ~5 ~10 - 20 ~10
Q - ~5 +5 ~5 650
3 (500 ~ 845)
~5 +5 - 15 . 5
0 ~ +7 ~5 - 15 5 - 10
Ev~3n during the first week from the beginning of ad
mini.~tration oî the ;pr~paration a considerable improv ement
o~ th~ patient~ ' state of health was noted: retro3ter~al
pain~, occurred les~ f'requentl~, dyspnea became less pxo-
nouIlced, ~he rate of admini~tration of ~itrogl;s~cerin
tablets per day wa~ sharpl;y reduced,, working capacit~ was
incre~sed~ weakness in leg~ disappear~, heart inter-
mis6ions became le~s frequentO
~ he eleGtrocardiographic investigations re~realed a
slight decrea~ of the rate of the heart ' ~ beat, di~ppea-
rance of auriculare snd ~rentricular ext:ras;y~toles3 rei;D-
22 -
s~
Yer~ion of the T ripple ~nd inc~ease of it~ posi tiYe smp-
litude. In the investigation o~ arterisl pressure there
wa~ observed the growth of all ki~ds of ~P, especiall~
the value of hemodynamic imp~ct which pointed to the
growth of kinetic energ~ of the hemod~amic flow. ~he
~rowth of the ~rterial pressure wa~ a~sociated mainly
with the increase of beat ejection~ whPrea~ the tonus of
vessels of ela~tic and mascular t~pe was not substantially
ch~nged which was demol~trated by the values of the pro-
pagation ~peed of the pulse w~ve~
In the phase analysis of the left ventricl2 duri~
the treatment the involution period ~ WAS definitel~ in-
creesed the phase of expul~ion E wa~ reduced, the period
of ten~ion PT shortened mainly due to a reduction of the
period of isometric contraction (IC).
~or evaluation of contraction properties of myo~ -
cardium ~eparately during its 8~5 tolic ~nd diastol~c pe-
riod~ o~ its co~traction there were used amplitude~time
ch~racteristics rate of heart e~ection (RH~), rate of
pressure raise ~BP~) a~d rate o~ heart relaxation ~RER)~
~ he rate of heart ejection (~E) i~ determined by the
fo~mula: B~6 , wherein BV - beat volume i~ ml~ E ~ time of
the expul~ion phase in second~O
~ he value o~ RHE characterizes contraction proper
tie~ of t~e myoc~rdium during the sy~tole period; incxease
of this v~lue in the course of treatment b~ means of the
prepar~tion according to the pre~ent invéntion demon~tra-
~e~ improYement of inotropic p~operties of m~ocardium.
- ~3 ~
The rate of pre~sure xsi~e i8 determined by the for-
mul~: RPR ~ wherein DP - diastolic pressure in mm,
C
Hg, 5 - co~entional value of ~he final diastolic pressure
in the aoxta, IC - isome~ric contraction. RPR characterized
contracti~e prop~rties of the m~ocardium during the period
of closed valves and it~ sbilit~ of rapidly surpassing
the value of pre~sure in the aorta for ope~ing of the
aortic valves.
The rate o~ beart relsxation (R~IR) characteri3es acti-
vity of the m~ocardium at the moment of diastole and is
determined b~ the foxmula: ~R = ~ , wherein SP -
~tolic pressure in -the brachial artery in mm ~,
5 - conventional value of the final diastolic pressure in
the aorta, D ~ duration of the diastolic period in secoIlds.
The re~ult~ of the inve~tig~tion are ~hown in ~able 7 hexein-
below.
The antianginal and ~ntiarrh~thmic effects of the pre-
paration accordin~ to the present invention were evaluated
with the use of the ln~ectional pharmaceutical form oX the
pr~psrstio~ administered intra~enously in an amou~t of 00 2
to 0.4 g based on the active principle~ In 8 cases of
ste~ocardia attack in 5 patients -the prep~ration rapidly
cut short retrosternal pain~ without an~ additional admi-
nistrstion of nitrates, analgetics and narcotics. However,
the analgetic effect was not alwa~s stable which necessits-
ted a repeated administratio~ of the preparationO
The prep~ration efficiency in the case of extrasysto-
lic srrh~thmia was studied on 7 patients~ ~he i~travenous
-24 -
,
.
5~
Variatio~ OI hemod;y~amic parameters in patients
with I~ID under the e~fect of ~M~m~ of the pero~al
form o~ the pharmaceu~ical compo~;ition containirlg
3- ( 2, 2, 2-trimet~;srlh;~rdra zinium)propi onate dihydrate
a6 the zctive principle
~abl e 7
Psrameter during the
b sf ore
Nos Parameker treatment 1 st week 2nd wee~
_ __ _~_ __ __
2 , ~ _ _ 4
2 beeat/m~s 72. 3~ 5 67 . 8+1 ,, 8 64. 3+'1 . 3
3 beat ~rolume,
l/min 70 ~ 2~5 .. ~ 72 ~ 2~3 . 7 74 0 4+~ . 7
. ~ minute blood
volume, 5.6+0.3 4.9~1.3 4.8~5.1
l/min
5 f inal ~ysto-
mm/Hg 130 ,.4+2. 0 134. 6+1. 6 143 . 5~1 . 8
6 lateral systo- 11508+0.5 1'16.4~2.1 1~l809~1~7
7. ~vera~e d~na- .
mic pres6ure 89 . 7~1 . 2 90 ~. 6~0 ~ 7 91 . 2~10 2
a d stol c 68 . 2+0 . 6 69 . 9+1 . ~ 70 0 3~0 r 9
9 pulse pres~ 47.6~0.6 46.5~1.1 48.~1.6
hemod;ynsmic '1*,.6~1.2 18.2~1.. 0~ 24.6~0.7
11 i~volution 830~26 . 873f33 933_~42b
'12 expulsion
phase,milli~ 222~4 . 225+2 230~3
13 te:~lsion period,
milliseeond~ '109-~4 .104+2 ~100~4
^5
.
~able 7 (cont.)
~ __ 4 5
14 as~nchxon.
contraction 56+2 55~4 54~2
i~ometric
contraction,
millisec. 53~2 49~3 46~4
16 diastol~,
milIiseconds 499~14 543~21 603~21
17 volume of
heart ejection,
ml~sec 315~15 320+23 322~13
18 rate of pres~
sure raise,
mm Hg/sec 1,188~30 1,326+45. 1~473~130
19 rate of heart
relax~tion,
mm Hg/sec 250~9 238~10 229~8
Note: certainty of difference p c 0.010
, -- 2b -- '
.
s~
~able 7
(contO)
Parameter during the treatment
~os ~
3rd week 4th week
_
2 60.1+176~ 62.2+1.4
3 ~0~6+405 8400~.4
4 4.~+307 5.2+3~5
~45.0~2.4~ ~50.6~2~7
6 120.1+1.4~ 125.6~007
7 92~0~1.8 92.2~1.0
8 7203+1.4 72.0~1~8¢
9 47.8+1.4 53.6+102
~0 24.9~.5~ 25.~+0.7
~1 1000+42~ 965~21
~2 232~4 ~35~3
13 99~3~ 88*2
14 56~4 55~3
43+2 33~2
16 669~14~ 642~14
~7 374+14~ 357+17
18 1,581~54~ 2,030+68
19 209~8 226~12
~ote: ~cartainty of differe~ce P - 0.01
~ 2?-
administration o~ the prep~ration (1 ml of a L~~ solu-
tion) arrested the rhythm disorder ~or 5-20 minutes.
~ herefore, the pharmaceutical preparation based on
3-(2,2,2-trimeth~lh~dr~zinium)propionate in patients
with verified ischemic disease provides the inotropic
effect on the myocardium, remo~es retrosternal pains
and rhythm disorders ~uch as extrasystole.
Consequently, the ph~rmaceutical preparation
according to the present invention fea-tures a special scope
of activit~; it m~nifests itself a~ a ~asodilative prepa-
ration relative to coronary arteries, facilitates imprQVe~
ment of the myocardial metabolism and posse6ses a clearly
pronounced and stable positi~e inotropic ef~ect.
~ he pharmaceutical preparation ac~ording to the pre-
sent invention is preferabl~ administered in the form of
injectio~ solutions, tablets~ capsules, powders. It is in-
dicated at the rate of 10 to ~0 m~kg of the bodyweight
as tablets or cap~ules per da~ simultaneously with taking
meals, or i~ the form of 10-40% injection solution~ ~he
preparaticn of the present invention relates to low-toxic
~ubsta~ces ~ist B or even les~ strict).
Pharmaceutical forms o~ thc preparation for peroral
administration are stable for two years at room temperatu-
re and are to be stored in a dry~ ht-protected place
Injection solutions should be stored for ~ot more than 2
years at a temperature of not more than +5C.
~ he active principle according to the present.in~en-
tion, vizo 3-(2,2,2-trimetylhydrazinium)propionate is
- 28 -
....
~ a ~s~
prepared b~ a~y conven~ional me~hod; for ex~mple, a solutiono~ methyl-3-(272~2~trimeth~lh~drazi~iu~pr~pion~te chloride in .
water is passed through a co1umn with an îon exchange resin
Amberli te IRA-400 /Registered ~rade Mark/. The solvent is re-
moved and the residue is cr~stallized from eth~nol~ ~here are
thus obtai~ed 140 g (85~) of 3-(2~2,2-trimethylh~draziniu~)
propionate in the form of colourless c~stals with the M.p.
of 254-256C. ~MR spectrum ( ~ , ppm): 6.79 sin~let,
(CH3)3~+; 6.89 triplet~ CH~; 7.77, triplet, CH2.
~ ound, %: C 39.56, ~ 10-10, ~ 15.36; C6H1~02~2~2~20
Calculated, %: C 39.56; H 9.89, N 15~30.
3 - ( 2 7 2~2 trimethyl~ydrasinium)propionate dih~drate
comprises ~ htl~ h~groscopic white substances well solub-
le in water, hot ethanol and methanol, insoluble in non-
polar solvents, having a weak specific odour. When stored
in closed ware at room temperature, it is stable fox at
2 ~ear~. ~pon heati~g above 40C the product loses crystsl-
lization water and slowl~ decomposes.
-- 29 -~
